This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. For this proposal, the hypothesis is that intensive ligand-based computational methods will yield improved understanding of the requirements for effective and selective CB1/CB2 inhibition and will provide a rational guide for novel CB ligand development. The specific aims are: Aim 1. Develop four classes of pharmacophore models for CB1 and CB2 agonists and antagonists, based on all CB ligand and activity data available in the literature. The pharmacophore models will be cross-compared to gain understanding of requirements for receptor selectivity. Aim 2. Use the best pharmacophore models from Aim 1 for virtual screening to identify novel CB ligands in the different categories. Aim 3. Using CB1 and CB2 in vitro activity data for novel ligands, develop quantitative structure-activity relationship (QSAR) models to aid understanding of the molecular basis for the activity and selectivity and to provide a rational guide to modification of ligands for enhanced activity and selectivity. Though not specifically emphasized in the original proposal, we are proceeding with limited modeling of the CB1 and CB2 receptor three-dimensional structure and ligand docking studies, in order to aid the ligand-based modeling studies of Aims 1 and 3 and to ensure that we have as comprehensive an approach as possible to the rational search for novel CB ligands.